U.S. patent application number 12/919842 was filed with the patent office on 2011-01-06 for process for preparing alkyl 2-alkoxymethylene-4,4-difluoro-3-oxobutyrates.
This patent application is currently assigned to BASF SE. Invention is credited to Michael Keil, Christopher Koradin, Volker Maywald, Michael Rack, Sebastian Peer Smidt, Bernd Wolf, Thomas Zierke.
Application Number | 20110004002 12/919842 |
Document ID | / |
Family ID | 39645697 |
Filed Date | 2011-01-06 |
United States Patent
Application |
20110004002 |
Kind Code |
A1 |
Maywald; Volker ; et
al. |
January 6, 2011 |
Process for preparing alkyl
2-alkoxymethylene-4,4-difluoro-3-oxobutyrates
Abstract
A process for preparing alkyl
2-alkoxymethylene-4,4-difluoro-3-oxobutyrates (VI) ##STR00001##
where R is methyl or ethyl, from crude reaction mixtures of alkyl
4,4-difluoroacetoacetates (I) ##STR00002## by a) reacting
##STR00003## where M is a sodium or potassium ion, and ##STR00004##
without additional solvent to form an enolate (V) ##STR00005## b)
releasing the corresponding alkyl 4,4-difluoroacetoacetate (I) from
the enolate (V) by means of acid, c) removing the salt formed from
cation M and acid anion as a solid and d) converting (I), without
isolation from the crude reaction mixture, to the alkyl
2-alkoxymethylene-4,4-difluoro-3-oxobutyrate (VI), and the use of
(VI) for preparing
1-methyl-3-difluoromethyl-pyrazol-3-ylcarboxyates VII
##STR00006##
Inventors: |
Maywald; Volker;
(Ludwigshafen, DE) ; Smidt; Sebastian Peer;
(Offersheim, DE) ; Wolf; Bernd; (Fussgoenheim,
DE) ; Koradin; Christopher; (Ludwigshafen, DE)
; Zierke; Thomas; (Boehl-Iggelheim, DE) ; Rack;
Michael; (Eppelheim, DE) ; Keil; Michael;
(Freinsheim, DE) |
Correspondence
Address: |
BRINKS, HOFER, GILSON & LIONE
P.O. BOX 110285
RESEARCH TRIANGLE PARK
NC
27709
US
|
Assignee: |
BASF SE
Ludwigshafen
DE
|
Family ID: |
39645697 |
Appl. No.: |
12/919842 |
Filed: |
February 27, 2009 |
PCT Filed: |
February 27, 2009 |
PCT NO: |
PCT/EP09/52378 |
371 Date: |
August 27, 2010 |
Current U.S.
Class: |
548/374.1 ;
560/177 |
Current CPC
Class: |
C07C 69/72 20130101;
C07C 67/343 20130101; C07C 67/343 20130101; C07D 231/14
20130101 |
Class at
Publication: |
548/374.1 ;
560/177 |
International
Class: |
C07D 231/14 20060101
C07D231/14; C07C 69/66 20060101 C07C069/66 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 29, 2008 |
EP |
08102197.4 |
Claims
1-10. (canceled)
11. A process for preparing an alkyl
2-alkoxymethylene-4,4-difluoro-3-oxobutyrate of the formula (VI)
##STR00015## where R is methyl or ethyl, from crude reaction
mixtures of alkyl 4,4-difluoroacetoacetate (I) ##STR00016## which
comprises a) initially charging two of the following components
(II), (III) and (IV) ##STR00017## where M is a lithium, sodium or
potassium ion, and ##STR00018## and reacting this mixture with the
third component to form an enolate of the formula (V) ##STR00019##
b) adding an acid to the reaction mixture to release the
corresponding alkyl 4,4-difluoroacetoacetate of formula (I) from
the enolate (V), c) removing the salt formed from cation M and the
acid anion as a solid and d) converting (I), without isolation from
the crude reaction mixture, to the alkyl
2-alkoxymethylene-4,4-difluoro-3-oxobutyrate of the formula
(VI).
12. The process according to claim 11, wherein process stage a) is
carried out by initially charging alkyl acetate (II) and alkyl
difluoroacetate (IV) and metering the alkoxide (III) in.
13. The process according to claim 11, wherein (I) is released from
(V) with exclusion of water or in the presence of a small water
content.
14. The process according to claim 11, wherein the acid used for
the release of (I) from (V) in process stage b) is hydrogen
chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, formic
acid, acetic acid, oxalic acid, citric acid, methanesulfonic acid,
or p-toluenesulfonic acid.
15. The process according to claim 11, wherein the release of (I)
from (V) in process stage b) is carried out in the presence of a
small water content.
16. The process according to claim 11, wherein the molar ratio of
alkyl acetate (II) to alkoxide (III) is from 0.8:1 to 10:1.
17. The process according to claim 11, wherein the molar ratio of
alkyl difluoroacetate (IV) to alkyl acetate (II) is from 1:0.8 to
1:20.
18. The process according to claim 11, wherein the molar ratio of
alkoxide (III) to acid is from 1:0.7 to 1:5.
19. The process according to claim 11, wherein the reaction
temperature for the reaction of (II), (III) and (IV) is from
-20.degree. C. up to 70.degree. C.
20. A method of preparing a
1-methyl-3-difluoromethyl-pyrazol-3-ylcarboxyate of the formula VII
##STR00020## comprising cyclizing the compound of formula VI
prepared in accordance with the process of claim 11.
21. The method of claim 20, wherein said cyclizing comprises
reacting the compound of formula VI with methylhydrazine.
Description
[0001] The present invention relates to a process for preparing
alkyl 2-alkoxymethylene-4,4-difluoro-3-oxobutyrates of the formula
(VI)
##STR00007##
where R is methyl or ethyl, from crude reaction mixtures of alkyl
4,4-difluoroacetoacetates of the formula (I)
##STR00008##
[0002] With respect to the preparation of I with R being ethyl, Y.
Desirant, Bulletin de la Societe Chim. Belg. 39 (1930) discloses
the reaction of a suspension of sodium ethoxide in dry ether first
with ethyl difluoroacetate and then with ethyl acetate, and the
release of ethyl 4,4-difluoroacetoacetate from the enolate formed
by means of 10% aqueous sulfuric acid. For this process, in the
best case, a yield of 65% is reported.
[0003] However, this process is not very suitable for an industrial
scale preparation of the alkyl
2-alkoxymethylene-4,4-difluoro-3-oxobutyrates (VI) since the yields
for the preparation of the alkyl 4,4-difluoroacetoacetates (I) are
unsatisfactory (due to some product being lost during purification
by destillation) and the reaction times of 5 days are unacceptably
long. Moreover, the handling of the ether used as the solvent would
be disadvantageous, since its very low boiling point would
necessitate complicated measures for preventing evaporation losses.
Moreover, this solvent tends to form peroxides, for which reason
special safety measures have to be taken.
[0004] Other processes for preparing alkyl
4,4-difluoroacetoacetates described in the literature have the
disadvantage that bases which are expensive and/or difficult to use
industrially, such as sodium hydride or lithium diisopropylamide,
are used (cf. McBee et al., J. Am. Chem. Soc., 75, 3152-3153 (1952)
and S. Jagodzinska et al., Tetrahedron 63, 2042-2046 (2007)), or
the reaction is carried out in an additional solvent to be handled
(WO 2007/115766, Example H1).
[0005] A process for the preparation of ethyl
2-ethoxymethylene-4,4-difluoro-3-oxobutyrate is disclosed in WO
2005/123690 (page 21, paragraph 2.)). However, the precursor
compound ethyl 4,4-difluoroacetoacetate is obtained according to
another method and purified by distillation before the further
conversion. These high temperatures, however, adversely affect the
yield of the ethyl
2-ethoxymethylene-4,4-difluoro-3-oxobutyrate.
[0006] It was accordingly an object of the invention to provide an
industrially simple process for preparing the alkyl
2-alkoxymethylene-4,4-difluoro-3-oxobutyrates (VI).
[0007] Accordingly, it has been found that the alkyl
2-alkoxymethylene-4,4-difluoro-3-oxobutyrates (VI) are obtainable
in high yields by [0008] a) initially charging two of the following
components (II), (III) and (IV)
[0008] ##STR00009## [0009] where M is a lithium, sodium or
potassium ion, and
[0009] ##STR00010## [0010] and reacting this mixture with the third
component without additional solvent to form an enolate of the
formula (V)
[0010] ##STR00011## [0011] b) releasing the corresponding alkyl
4,4-difluoroacetoacetate of the formula (I)
[0011] ##STR00012## [0012] from the enolate of (V) by means of
acid, [0013] c) removing the salt formed from cation M and the acid
anion as a solid and [0014] d) converting (I), without isolation
from the crude reaction mixture, to the alkyl
2-alkoxymethylene-4,4-difluoro-3-oxobutyrate of the formula
(VI).
[0015] The starting compounds (II), (III) and (IV) are commercially
available or can be prepared in a manner known per se.
[0016] Preferably, the alkyl acetate (II) and alkyl difluoroacetate
(IV) are initially charged and the alkoxide (III) is metered
in.
[0017] The amount of alkyl acetate (II) is such that the reaction
mixture with alkoxide (III) and alkyl difluoroacetate (IV) either
gives rise to a readily stirrable suspension or becomes
homogeneous. Advantageously, the molar ratio of alkyl acetate (II)
to alkoxide (III) is from 0.8:1 to 10:1, especially from 2:1 to
4:1, most preferably from 2.3:1 to 3:1.
[0018] The molar ratio of alkyl difluoroacetate (IV) to alkyl
acetate (II) is preferably from 1:0.8 to 1:20, especially from 1:2
to 1:3.
[0019] The metered addition of (II), (III) and (IV) typically
proceeds over the course of from 0.1 to 20 hours, especially from
0.5 to 5 hours, more preferably from 0.5 to 3 hours.
[0020] The reaction temperature for the reaction stage a) is
generally from -20.degree. C. up to the boiling point of the
reaction mixture, especially from 0 to 70.degree. C.
[0021] The reaction can be carried out under standard pressure or
under slightly elevated or reduced pressure. Typically, standard
pressure is employed.
[0022] The alkyl 4,4-difluoroacetoacetate (I) is released from the
enolate (V) in the presence of an acid such as hydrogen chloride,
hydrogen bromide, hydrogen iodide, sulfuric acid, formic acid,
acetic acid, oxalic acid, citric acid, methanesulfonic acid, or
p-toluenesulfonic acid, preference being given to hydrogen
chloride, in particular gaseous hydrogen chloride.
[0023] According to the present invention, the release of the alkyl
4,4-difluoroacetoacetate (I) from the enolate (V) is undertaken
with an anhydrous acid or an acid with only a small water
content.
[0024] A small water content is understood to mean from about 0.5 g
to 5 g of water per mole of alkyl difluoroacetate (IV) used.
[0025] In this procedure, it may be advantageous to remove the
inorganic salt formed from cation M and the acid anion in the
course of the neutralization before the further processing of (I),
for example, by means of filtration methods. With regard to the
filtration of the salt, a particularly advantageous procedure is
that in the presence of a small water content (for example when the
HCl gas is introduced or when an acid with a small water content is
used, such as conc. sulfuric acid). This generally gave rise to
significantly shorter filtration times, which may be highly
advantageous for the procedure on the industrial scale.
[0026] However, larger amounts of water should be avoided, unless
the subsequent removal of an aqueous phase is intended, since the
water would be troublesome in the conversion of (I) to (VI) or
would lead to an increased consumption of feedstocks (orthoester
and anhydride).
[0027] The amount of acid itself is not particularly critical. In
general, from 0.7 to 5 mol of acid are used per mole of alkoxide
(III) used, preferably from 0.8 to 2 mol of acid per mole of (III),
more preferably from 0.9 to 1.3 mol of acid per mole of (III).
[0028] The release of (I) from (V) by means of acid (stage b)) is
effected generally at from -10 to 50.degree. C., especially from 5
to 30.degree. C., and at standard pressure or slightly elevated
pressure, up to about 3 bar.
[0029] According to the process of the present invention, the alkyl
4,4-difluoroacetoacetate (I), in the alkyl acetate (II) after
removal of the inorganic salt and without purification, is reacted
directly with orthoester (HC(OR).sub.3) and acetic anhydride to
give the alkyl 2-alkoxymethylene-4,4-difluoro-3-oxobutyrate
(VI)
##STR00013##
[0030] The conversion of (I) to the alkyl
2-alkoxymethylene-4,4-difluoro-3-oxobutyrate (VI) is effected
normally at from 25 to 150.degree. C. and at standard pressure or a
slightly elevated pressure up to about 3 bar, especially at from 90
to 115.degree. C. and standard pressure.
[0031] The molar ratio of orthoester to alkyl
4,4-difluoroacetoacetate (I) is preferably from 1:1 to 3:1,
especially from 1.5:1 to 1.9:1.
[0032] When calculating the amount of acetic anhydride required for
a complete conversion, the alcohol formed from the alkoxide (III)
additionally has to be considered.
[0033] Typically, the amount of acetic anhydride is from 2 to 8 mol
per mole of alkyl 4,4-difluoroacetoacetate (I).
[0034] The process products (VI) are valuable intermediates for
preparing 1-methyl-3-difluoromethylpyrazol-4-ylcarboxylates
(VII)
##STR00014##
which are obtainable, for example, by cyclizing (VI) with
methylhydrazine (see U.S. Pat. No. 5,093,347, EXAMPLE 1).
1-Methyl-3-difluoromethylpyrazol-4-ylcarboxylates in turn are
important starting materials for preparing fungicidally active
pyrazol-4-ylcarboxamides.
WORKING EXAMPLES
Example 1
a) Ethyl 4,4-difluoroacetoacetate (Release from the Enolate with
Gaseous Hydrogen Chloride in the Presence of a Small Amount of
Water)
[0035] 733.1 g (8.32 mol) of ethyl acetate and 397.6 g (3.2 mol) of
ethyl difluoroacetate (99.9%) were initially charged at 25.degree.
C. and 238.7 g (3.437 mol) of sodium ethoxide (98%) were metered
form 25 to 65.degree. C. with stirring in the course of 1.3
hours.
[0036] Thereafter, the reaction mixture was stirred at 65.degree.
C. for a further 2 hours and then cooled to 25.degree. C.
[0037] To the resulting solution, 8 g (0.444 mol) water were added.
Then, at 25 to 31.degree. C., 160.5 g (4.40 mol) of HCl gas were
introduced within 2 hours, which formed a suspension (precipitation
of sodium chloride). Subseqently, a small amount (133.2 g) of low
boilers (133.2 g; ethanol, ethyl acetate; excess HCl) were removed
by destillation (internal temperature: 25-34.degree. C.; pressure:
150 mbar). The precipitated sodium chloride was filtered off and
the solid was washed four times with 360 g of ethyl acetate.
[0038] The resulting filtrate (2171 g) comprised 22.6% by weight of
the desired product of value (GC analysis, quantification with
internal standard).
[0039] The yield, based on ethyl difluoroacetate used, was 92.4%.
[0040] b) Conversion of ethyl 4,4-difluoroacetoacetate to ethyl
2-ethoxymethylene-4,4-difluoro-3-oxobutyrate
[0041] 2274.9 g of acetic anhydride (22.08 mol) were initially
charged in a stirred vessel and heated to 110.degree. C. Within 2
hours, 2171 g of the ethyl 4,4-difluoroacetoacetate solution from
synthesis example 1a) (22.6% solution in ethanol/ethyl acetate) and
822.7 g (5.44 mol) of triethyl orthoformate (98%) were metered in
in parallel. After about half had been fed in, reflux set in. At
the end of the metered addition, the internal temperature was
95.degree. C. The mixture was stirred at reflux temperature for a
further 7 hours and then cooled to 25.degree. C. At a pressure of
150 mbar, the low boilers (ethyl acetate, acetic acid, acetic
anhydride, triethyl orthoformate) were distilled off at internal
temperature 40-90.degree. C. To complete the removal, the pressure
was lowered to 5 mbar at 90.degree. C., and the distillation
bottoms were subsequently stirred at 95.degree. C./5 mbar for 0.5
hours. The obtained distillation residue (658.8 g) comprised 95.5%
by weight of the desired ethyl
2-ethoxymethylene-4,4-difluoro-3-oxobutyrate. This corresponds to
an overall yield over the two synthesis stages of 88.5% based on
the ethyl difluoroacetate used in working example 1a).
Example 2
Ethyl 4,4-difluoroacetoacetate (Release from the Enolate with
Gaseous Hydrogen Chloride)
[0042] 141.2 g (1.6 mol) of ethyl acetate were initially charged at
25.degree. C. and 45.9 g (0.66 mol) of sodium ethoxide (98%) were
added with stirring. After the suspension had been cooled to
5.degree. C., 76.7 g (0.6 mol) of ethyl difluoroacetate (97%) were
metered in at internal temperature from 5 to 13.degree. C. within
2.83 hours. Thereafter, the reaction mixture was heated to
65.degree. C., stirred at this temperature for a further 2 h and
then cooled to 20.degree. C. (264.3 g of solution).
[0043] At 21 to 31.degree. C., 26.5 g (0.726 mol) of HCl gas were
introduced within 30 minutes, which formed a suspension
(precipitation of sodium chloride). 51.2 g of ethyl acetate were
added to the suspension and then 21.2 g of low boilers were
distilled off at internal temperature 31.degree. C. and a pressure
of 150 mbar (removal of excess hydrogen chloride). After 5 g of
kieselguhr (filtration aid) had been added, the precipitated sodium
chloride was filtered off and the solid was washed with ethyl
acetate. The resulting filtrate (438 g) comprised 20.9% by weight
of the desired product of value (GC analysis, quantification with
internal standard).
[0044] The yield (based on ethyl difluoroacetate used) was
91.9%.
Example 3
Ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutyrate
[0045] 427.8 g of acetic anhydride (4.15 mol) were initially
charged in a stirred vessel and heated to 110.degree. C. Within 2
hours, 438 g of crude ethyl 4,4-difluoroacetoacetate from synthesis
example 2 (20.9% solution in ethanol/ethyl acetate) and 145.3 g
(0.96 mol) of triethyl orthoformate were metered in in parallel.
After about half had been fed in, reflux set in at 106.degree. C.
At the end of the metered addition, the internal temperature was
94.degree. C. The mixture was stirred at reflux temperature for a
further 6 hours and then cooled to 25.degree. C. At a pressure of
150 mbar, the low boilers (ethyl acetate, acetic acid, acetic
anhydride, triethyl orthoformate) were distilled off at internal
temperature 40-90.degree. C. To complete the removal, the pressure
was lowered to 10 mbar at 90.degree. C., and the distillation
bottoms were subsequently stirred at 95.degree. C./10 mbar for 1
hour. The distillation residue (125.7 g) comprised 89.7% by weight
of the desired ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutyrate.
This corresponds to an overall yield over the two synthesis stages
of 84.6% based on the ethyl difluoroacetate used in working example
2.
Example 4
Ethyl 4,4-difluoroacetoacetate (Release from the Enolate with
Methanesulfonic Acid)
[0046] 47.06 g (0.533 mol) of ethyl acetate were initially charged
at 25.degree. C. and 15.3 g (0.22 mol) of sodium ethoxide (98%)
were added with stirring. After the suspension had been cooled to
5.degree. C., 25.6 g (0.2 mol) of ethyl difluoroacetate (97%) were
metered in at internal temperature from 5 to 13.degree. C. within
2.83 hours. Thereafter, the reaction mixture was heated to
65.degree. C., stirred at this temperature for a further 2 hours
and then cooled to 20.degree. C. (88.1 g of solution).
[0047] At from 20 to 30.degree. C., 21.2 g (0.22 mol) of
methanesulfonic acid were added dropwise within 40 minutes, which
formed a thick suspension (precipitation of sodium
methylsulfonate). To dilute the suspension, 60 ml of ethyl acetate
were added. The solid was filtered off and washed twice with ethyl
acetate. The filtrate (209.2 g) comprised 13.9% by weight of the
desired product of value (GC analysis: quantification with internal
standard). The yield (based on ethyl difluoroacetate used) was
87.6%.
Example 5
Ethyl 4,4-difluoroacetoacetate (Release from the Enolate with
Sulfuric Acid (98%))
[0048] 45.9 g (0.53 mol) of ethyl acetate were initially charged at
25.degree. C. and 14.96 g (0.22 mol) of sodium ethoxide (98%) were
added with stirring. After the suspension had been cooled to
5.degree. C., 24.9 g (0.2 mol) of ethyl difluoroacetate (99.88%)
were metered in at internal temperature from 10 to 25.degree. C.
within 2.0 hours. Thereafter, the reaction mixture was heated to
65.degree. C., stirred at this temperature for a further 2 hours
and then cooled to 20.degree. C.
[0049] 20.4 g (0.2 mol) of sulfuric acid (98%, comprises 2% water)
were metered into the solution (85.6 g) at from 20 to 25.degree. C.
within 20 minutes, which formed a thick suspension (precipitation
of sodium hydrogensulfate). The precipitated salt was also filtered
off and the solid was washed with ethyl acetate. The filtrate
(166.1 g) comprised 19.1% by weight of the desired product of value
(GC analysis, quantification with internal standard). The yield
(based on ethyl difluoroacetate used) was 95.6%.
Example 6
Ethyl 4,4-difluoroacetoacetate (Release from the Enolate with
Formic Acid)
[0050] 47.06 g (0.533 mol) of ethyl acetate were initially charged
at 25.degree. C. and 15.3 g (0.22 mol) of sodium ethoxide (98%)
were added with stirring. After the suspension had been cooled to
5.degree. C., 25.6 g (0.2 mol) of ethyl difluoroacetate (97%) were
metered in at internal temperature from 5 to 13.degree. C. within
2.83 hours. Thereafter, the reaction mixture was heated to
65.degree. C., stirred at this temperature for a further 2 h and
then cooled to 20.degree. C. (88.1 g of solution).
[0051] At 20.degree. C., 10.3 g (0.22 mol) of formic acid were
added dropwise within 40 minutes which formed a suspension
(precipitation of sodium formate). The mixture was stirred at
25.degree. C. for a further hour. The precipitated solid was
filtered off and washed with ethyl acetate. The resulting filtrate
(160.6 g) comprised 18% by weight of the desired product of value
(GC analysis, quantification with internal standard). The yield
(based on ethyl difluoroacetate used) was 87.1%.
Example 7
Ethyl 4,4-difluoroacetoacetate (Release from the Enolate with
Gaseous Hydrogen Chloride in the Presence of a Small Amount of
Water)
[0052] 137.8 g (1.56 mol) of ethyl acetate were initially charged
at 25.degree. C. and 44.9 g (0.65 mol) of sodium ethoxide (98%)
were added with stirring. After the suspension had been cooled to
5.degree. C., 74.8 g (0.6 mol) of ethyl difluoroacetate (99.88%)
were metered in at internal temperature from 10 to 25.degree. C.
within 2.0 hours. Thereafter, the reaction mixture was heated to
65.degree. C., stirred at this temperature for a further 2 hours
and then cooled to 20.degree. C. (256.8 g of solution).
[0053] 0.3 g of water was added to the solution (256.8 g) and then
27.7 g (0.759 mol) of HCl gas were introduced at from 21 to
31.degree. C. within 30 minutes, which formed a suspension
(precipitation of sodium chloride). 22.1 g of ethyl acetate were
added to the suspension and then 14.2 g of low boilers (removal of
excess HCl) were distilled off at internal temperature 33.degree.
C. and a pressure of 150 mbar. The precipitated sodium chloride was
filtered off and the solid was washed with ethyl acetate. The
resulting filtrate (356.3 g) comprised 26.6% by weight of the
desired product of value (GC analysis, quantification with internal
standard).
[0054] The yield (based on ethyl difluoroacetate used) was
94.6%.
Example 8
Ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutyrate
[0055] 365.2 g of acetic anhydride (3.54 mol) were initially
charged in the stirred vessel and heated to 110.degree. C. Within 2
hours, 356.3 g of crude ethyl 4,4-difluoroacetoacetate from
synthesis example 7 (26.5% ethyl 4,4-difluoroacetoacetate solution
in ethanol/ethyl acetate) and 154.4 g (1.02 mol) of triethyl
orthoformate were metered in in parallel. After about half had been
fed in, reflux set in at 106.degree. C. At the end of the metered
addition, the internal temperature was 92.degree. C. The mixture
was stirred for a further 5 hours at reflux temperature and then
cooled to 25.degree. C. At a pressure of 150 mbar, the low boilers
(ethyl acetate, acetic acid, acetic anhydride, triethyl
orthoformate) were distilled off at internal temperature from
40-90.degree. C. To complete the removal, the pressure is lowered
to 5 mbar at 90.degree. C., and the distillation bottoms are then
stirred at 95.degree. C./5 mbar for 1 hour. The resulting
distillation residue (127.5 g) comprised 90.7% by weight of the
desired ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutyrate. This
corresponds to an overall yield over the two synthesis stages of
86.6% (based on the ethyl difluoroacetate used in working example
7).
* * * * *